The proposal describes a 5-year plan to study the interaction between antiarrhythmic drugs and cardiac sodium channels with an ultimate goal of obtaining insights for a better pharmacologic intervention for deadly arrhythmia. It also serves as a training program for the development of an academic career for the principal investigator as a physician scientist. The principal investigator has completed cardiology and postdoctoral fellowships under the guidance of Dr. Harry A. Fozzard at the University of Chicago and will proceed to lead an independent program in basic cardiac electrophysiology. Dr. Fozzard, who will continue to mentor the principal investigator's development, is one of the pioneers in modern basic cardiac electorphysiology and has trained numerous fellows and students, who have since become prominent researchers throughout the world. The Advisory Committee of highly regarded basic and clinical scientists will provide both scientific and career guidance. Research program focuses on the paths through which antiarrhythmic drugs bind and unbind the voltage-gated sodium channel to modulate the use-dependent block. The proposal builds on the foundations of prior studies in Dr. Fozzard's and other laboratories and uses the framework developed by the principal investigator recently. The specific aims include; 1) the effects of membrane depolarization, often seen in ischemia, on the drug-channel interaction of lidocaine and related compounds, 2) identification of other drug-paths to better characterize the drug-channel interactions and gain further insights into the structure of sodium channel, 3) examine the drug-paths important for use-dependent activities of other classes of antiarrhythmic drugs, and 4) expand into the preliminary findings suggesting that a long-QT mutation in the sodium channel alters drug-paths and consequently use-dependent properties of certain antiarrythmic drugs. The University of Chicago, an institution of international prominence in medical and basic science provides a rigorous academic environment with extensive resources for fostering a successful academic career.